Invest in ME Conference 12: First Class in Every Way
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B6 - sphingolipids, heme, detox, immune function, oh my!

Discussion in 'General ME/CFS Discussion' started by Learner1, Jan 10, 2017.

  1. Learner1

    Learner1 Professional Patient

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    I'm newer here and poked around to see if this was discussed anywhere else and didn't see it, so I'm hoping this is the right place to post this....

    Does B6 matter?

    I've had high serum ferritin for over a year. My doctor thinks it's due to my chronic infections, but ran an iron study to be sure. The results I had indicated either hemochromatosis or B6 deficiency anemia. I'm compound heterozygous for the 2 common HFE mutations, but my doctor said most people he'd seen with it had serum ferritin over 1000, which mine wasn't.

    Hematocrit, MCHC, and sed rate had dropped, which seem to be related - looked like B6 deficiency was impacting heme metabolism, so hemoglobin wasn't picking up iron to be able to carry oxygen around in my red blood cells, which were misshapen.

    We decided to up my P5P dose to 400mg, and sure enough my iron numbers are normalizing... BUT...

    I reviewed my lab results for the past 5 years, and it turns out, this is the 4th time it's happened! Each time B6 fixed it, with ever larger doses. (My memory wasn't so good til I looked back...and remembered the details through the fog...)

    My mom and child have had B6 problems, too, with a tendency to pick up toxins, and crappy methylation genes and glutathione production. The explanation I keep getting from our docs is it's used everywhere in methylation to detox, so we use it up fast.

    But 400mg a day feels ridiculous...

    I started digging into what B6 does and was quite surprised. B6 does a LOT of things...

    One thing is that it's instrumental in sphingolipid production.

    Which leaves me wondering if perhaps my sphingolipid production has been crappy for the past 5 years, leading to my CFS problem....

    It also seems to be instrumental in antibody production, and my immune system seems to be asleep at the wheel...

    Does any of this resonate with any of you? With the hundreds of posts I've seen here on PR on methylation, glutathione, and other Bs, I just haven't noticed much on B6 and wonder if it's important to anyone else but me.

    The sphingolipid piece makes me wonder in light of Naviaux's recent findings...

    Thanks for any thoughts or comments ...
     
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  2. alicec

    alicec Senior Member

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    It's certainly important to me.

    There have been a number of threads discussing B6. There seems to be two camps of people - those who are very sensitive and either can't tolerate it or can take just tiny doses. Some of these people experienced the neurotoxicity associated with very high doses even from relatively low doses. See here.

    Then there are the people who definitely benefit from sometimes high doses. I am in this camp.

    In the same thread I just linked there is some discussion about the interaction of B6, B2, magnesium, boron etc, along with a consideration of functional B6 deficiency, starting here.

    I first increased B6 dose because of oxalate issues. In this context, your 400 mg/day is not ridiculous. Doses of 300 mg or more are often recommended to deal with oxalate accumulation. I took about 300 mg/day for quite some time, along with other recommended things and it did seem to resolve my oxalate problems.

    I then cut back to about 50 mg/day but more recently have found that I have benefited considerably from increased dose again. I have gone back to up to 300 mg/day, still trying to decide what dose to settle on.

    It is interesting that you seem to have such a high need for B6 and that possibly this is something that others in your family share.

    In the oxalate case, there are rare genetic defects in certain enzymes that can be the cause of the problem, but more often it is acquired. Factors behind this are not well understood but one that has been studied is chronic oxidative stress causing conformational changes in the enzymes which process oxalate precursors.

    The change applies to all B6-dependant enzymes, not just those involved in oxalate processing. Anyhow, B6 dependent enzymes are homo-dimers held together by B6. Conformational change means they can no longer bind B6 properly. Thus the enzyme doesn't assume the right shape and so cannot function well.

    B6 might be available but it is not able to do its job properly. There is a functional deficiency. Adding large amounts of B6 seems to be able to overcome the problem at least in part by strongly driving the poorly functioning enzyme. The same thing usually works for the genetically altered enzyme also.

    Perhaps in your case it is also a problem with one of more B6 dependent enzymes which can be overcome by the high doses, or alternatively some other problem is driving excessive B6 consumption.

    Here and here are a couple of posts in a different context which may be of interest.

    Thank you for reminding us of the importance of B6 in sphingolipid biosynthesis. I had forgotten about that.
     
  3. Gingergrrl

    Gingergrrl Senior Member

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    I plan to re-read this thread later b/c there is so much good information in it! B6 was one of the supplements that was recently recommended for me (but at a very tiny dose, alternating every few days). I need to re-read my notes b/c I do not remember the exact dose or schedule.

    There were three supps recommended for me and B6 was one of them. Without my notes, I do not remember why, but it was based on my Metabolon results. Sorry this is all so vague and I am bookmarking this thread so I can return to it later.

    I am supposed to start the supplements one at a time, and B6 was the last of the three, and I have not actually tried it yet. I want to learn more so I can understand it better. I did not do well with B12 in the past but have no idea how I might react to B6?
     
    Last edited: Jan 12, 2017
  4. Learner1

    Learner1 Professional Patient

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    Thank you for taking the time to share the links and explanation... very helpful.

    From the discussion I saw, and my experience, I'd bet some people are either missing cofactors or they have significant toxicity.

    I'm on a well supervised custom methylation protocol, with vast amounts of B12 and every cofactor mentioned, except I may need to check on boron. And the B6 I take is all P5P.

    So, with the floodgates open, I'm still sucking up B6 and B12 in vast amounts, with a high need for B2.

    I'm too tired to dig further now, but it seems B6 is incredibly important, and with the number of people commenting on it, I wonder if it is indeed related to Naviaux's sphingolipid findings along with the B2 and B12 defiencies....

    But that's the work of another day ...

    Thanks again.
     
    MEMum likes this.
  5. alicec

    alicec Senior Member

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    Other trace minerals may also become depleted - copper, molybdenum, manganese particularly.

    After the mineral depletion experience, I found I had depleted biotin. Big doses opened up new floodgates and I started sucking up these same B vitamins and a new round of sucking up trace minerals.

    Here is the first of a couple of posts on my depletion experiences - several more in the same thread including a link to the refeeding thread which may help to explain some of this phenomenon, plus another summarising post.

    Since that post I have started sucking up B6 again. It seems to go on endlessly!

    We must have so many metabolic blockages and disturbances. Finding something that unblocks one just exposes many more.
     
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  6. Learner1

    Learner1 Professional Patient

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    Good points - thank you for the detail. It may be we'RE on to the next blockage.

    I take them all and am pretty closely monitored, and have developed a good respect for balancing cofactors.

    I think I'm using it up in Phase II detox, struggling immune system, and trying to make sphingolipids, none of which my body is terrifically good at... I have unhappy mitochondria, so am wondering how that plays in, too.
     
    Last edited: Jan 11, 2017
  7. Learner1

    Learner1 Professional Patient

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    This describes PLP (P5P or B6) and it's importance in sphingolipids and immune function.

    http://www.folk.uib.no/mfapu/Pages/papers pdf/2013/paul_2013_nr_71-239.pdf

    I extracted this from the PDF:

    PLP-dependent metabolism of sphingolipids

    Reduced availability of PLP is associated with reduction
    in several components of the immune response, includ-
    ing significant decreases in lymphocyte numbers, espe-
    cially T-helper cells and IL-2 production in humans.6
    Lymphocytes isolated from vitamin B6-deficient subjects
    also show reduction of lymphoproliferative responses to
    mitogens that activate both T and B cells when grown in
    a culture medium containing adequate concentration of
    PLP.6 This has been attributed to the lower numbers of
    T-helper cells in the lymphocyte population from vitamin
    B6-deficient subjects. Maturation and egress of lympho-
    cytes, especially T-cells, from thymus and lymph nodes
    relies on the gradient of sphingosine-1-phosphate (S1P).
    PLP-dependent enzymes play a major role in the synthe-
    sis and breakdown of S1P, which is a potent metabolite
    that regulates inflammation and immune response pro-
    cesses such as cell growth, survival, differentiation, lym-
    phocyte trafficking, vascular integrity, and cytokine
    and chemokine production.58,59 PLP is required for the
    activity of serine palmitoyl transferase that catalyzes the
    condensation of serine and palmitoyl CoA into 3-keto-
    dihydrosphingosine, which is then converted to S1P
    in a series of reactions.58–60 PLP is also a cofactor for
    sphingosine-1-phosphate lyase, which irreversibly cleaves
    S1P to regulate its concentration.58,59,61 A gradient of S1P
    is required for lymphocyte egress from thymus and
    peripheral lymphoid organs, which is maintained by S1P
    lyase.62 Administration of vitamin B6 antagonist 4’ deoxy-
    pyridoxine interferes with the S1P gradient, results in
    accumulation of mature lymphocytes in the thymus, and
    depletes B- and T-lymphocytes from lymph causing lym-
    phopenia.62 These conditions can be reversed by provid-
    ing excess vitamin B6 in the diet.62 During inflammation,
    S1P concentration increases in the inflamed peripheral
    tissues,63 which functions as a chemoattractant for the
    inflammatory cells.
    One of the intermediate products during the synthe-
    sis of S1P from 3-keto-dihydrosphingosine is ceramide,
    which plays an important role in inflammatory processes.
    Ceramide functions as a second messenger mediating the
    effects of tumor necrosis factor-a and interferon-g on
    programmed cell death and regulating senescence.64,65 An
    increase in cellular ceramide concentration is observed in
    cystic fibrosis, experimental autoimmune encephalomy-
    elitis, and diet-induced insulin resistance, all of which are
    marked by chronic inflammation.66–68 The importance of
    ceramide in these diseases is demonstrated by the fact
    that manipulation of ceramide concentration via inhibi-
    tion of serine palmitoyl transferase or mutation of sph-
    ingomyelinase, reverses the pathology of the disease.66–68
    Ceramide-1-phosphate, which is derived from ceramide,
    activates mast cells that mediate inflammation.69
    Thus, it is possible that is a higher demand exists for
    PLP during inflammation due to the role of PLP in the
    synthesis of S1P and ceramide, and maintenance of S1P
    gradient.
     
  8. eljefe19

    eljefe19

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    @Learner1 Woah that's as close to a theory of everything that I've seen, elucidating multiple system failures caused by ME/CFS. Great find. Paging @nandixon

    Also there's discussion about S1P on the big thread on the latest F&M research. You should post this there.
     
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  9. Learner1

    Learner1 Professional Patient

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    Thank you! I copied it over on the long Naviaux Metabolomics thread, hope that's where you meant.
     
  10. Mary

    Mary Senior Member

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    When I had Nutreval testing done close to 7 years ago, my need for B6 registered at a 9 (the most severe deficiency was a 10). I think B12 was an 8 or so. I've been tsking P-5-P ever since, and have found that 100 mg works for me. One of my sisters (who does not have ME/CFS) did have symptons of pyroluria, most notably an inability to get any color in her skin from the sun, though as a child she got quite dark. After several months of taking P-5-P, she began to sunburn a little. So there may be a genetic component here.
     
  11. alicec

    alicec Senior Member

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    Yes thanks for that. The Naviaux thread seems to have died down but there is a lot of discussion on a more recent thread about a paper from Fluge and Mella. Currently the discussion has focused on S1P. I am sure you would find it interesting and you might like to post this study there also or draw their attention to this post.
     
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  12. Gondwanaland

    Gondwanaland Senior Member

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    Another important nutrient for sphingolipid production is vitamin K2-MK4.
     
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  13. Learner1

    Learner1 Professional Patient

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    Yes, I've been at 10 for both B6 and B3 on my NutrEval. Not always, but sometimes. My daughter, too.

    Any clue as to which genetic component? We have an assortment of unsavory methylation SNPs...
     
  14. Learner1

    Learner1 Professional Patient

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    Great! Anything else to add to the list?
     
  15. Learner1

    Learner1 Professional Patient

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    I put it there. Do you know where I can learn to quote and share better with this app? (I'm a brain fogged Luddite....)

    Thank you for the guidance!
     
  16. Mary

    Mary Senior Member

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    Sorry, no idea. It just struck me that I was so deficient in B6 (despite having taken a B complex for years and years) and my sister had a condition which involved an apparent B6 deficiency (as well as a couple of other things). But we have extremely different in manifestations of low b6. I have ME/CFS, she doesn't. My energy increased noticeably when I added in P-5-P though I had no trouble getting sunburned! Whereas no matter how much my sister was in the sun, her skin had a white pallor - and she used to tan very easily when young. And she got some color from the sun for the first time in several years after starting the P-5-P.
     
  17. Learner1

    Learner1 Professional Patient

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    B6 is used in many pathways, so it's not surprising that it would show up differently.

    I knew about B6 and the detox pathways, but it's use in the immune system and sphingolipid metabolism may be more important in CFS.

    As with anything, there will be cofactors. Aside from K2, I'm wondering what they're be and whatever the pathways look like. trying to figure out what's sucking up all this B6.

    I found this article which may have an explanation for the paleness...I'd fact check it all, though...

    http://www.health-science-spirit.com/pyroluria.htm

    Lots to learn...
     
  18. Gondwanaland

    Gondwanaland Senior Member

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    As you said above, there is a whole cascade of minerals and interacting nutrients. My current experiments point to a protease deficiency for me - I believe that breaking protein down is the 1st function of B6 in the body and wonder how B6 and protease interact.

    Tanning involves copper bioavailability
     
  19. Mary

    Mary Senior Member

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    Pale skin and poor tanning are also symptoms of pyroluria which usually involves excess copper. My sister had other symptoms of pyroluria as well.
     
  20. alicec

    alicec Senior Member

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    The whole pyroluria thing needs a lot of fact checking. Unfortunately when you try to do this often there are no facts to be found. See this thread.
     
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